Metformin and Simvastatin in Addition to Fulvestrant

NCT03192293 | Unknown Phase 2

• 2 other identifiers: BR03/10/162016/01178
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective single arm open-label Phase 2 study utilising the combination of Fulvestrant, Metformin and Simvastatin in post-menopausal ER-positive metastatic breast cancer, with the primary endpoint being Clinical Benefit Rate (defined as complete response, partial response or stable disease, equal to or more than 24 weeks). The hypothesis is that the addition of Metformin and Simvastatin to Fulvestrant will improve the Clinical Benefit Rate from 40% (historical data from control arm of PALOMA-3 study) to 60%. A total of 28 patients will be enrolled over a period of 24 months. Eligible patients will receive 500 mg Fulvestrant by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days). Patients will be given 850mg oral Metformin twice-a-day (based on xenograft models which showed that Metformin had anti-tumor effects at a minimum dose of 1500mg per day), and 20mg oral Simvastatin every night (drawing reference from the investigators' group's window-of-opportunity study), daily throughout the cycle. As part of the in-build safety and tolerability design, all patients will have a lead-in period of 7 days where they receive 850mg oral Metformin twice-a-day and 20mg oral Simvastatin every night. Special adverse events of interest include lactic acidosis, diarrhea, bloatedness, transaminitis and rhabdomyolysis. If no dose-limiting toxic effects (DLT) occur, Fulvestrant will be commenced, and considered the start of cycle 1. If DLT occurs in any of the patients, the combination of Metformin and Simvastatin will be modified for the affected patient as per protocol, with further monitoring for another 7 days. This combination will be deemed safe for that patient if no DLT occurs, following which cycle 1 can officially commence. At the time of study entry, blood samples will be drawn to establish baseline physiological parameters including fasting insulin, glucose, lipids and Homeostasis Model Assessment 2 (HOMA2). In patients who have accessible tumor sites and are willing to provide tissue for translational research, pre- and post-treatment (at end of 8 weeks) biopsies will be taken for correlative biomarker studies. Patients will be evaluated on an 8-weekly basis for toxicities and efficacy assessments during the first 6 months of treatment, followed by 12-weekly thereafter until disease progression, unacceptable toxicities, or patient withdrawal.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Clinical benefit rate (CBR)

  the percentage achieving CR, PR and SD in patients with measurable disease or the absence of disease progression in patients with non-measurable disease, lasting at least 24 weeks.

  The Clinical Benefit Rate will be assessed at 24 weeks of treatment with study drug. The time frame will be through study completion, in an average of 2 years.

Secondary Outcomes (3)

• Objective response rates (ORR)

  The Objective Response Rate will be assessed from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed through study completion, in an average of 2 years.

• Progression-free survival (PFS)

  The progression-free survival will be assessed from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed through study completion, in an average of 2 years.

• Presence of toxicities

  The presence of toxicies will be monitored through study completion, in an average of 2 years.

Study Arms (1)

Metformin/Simvastatin/Fulvestrant

EXPERIMENTAL

7 days Lead-in period: 1. Metformin: 850mg (one tablet) twice a day 2. Simvastatin: 20mg (one tablet) once every night Once the doctor has deemed that patients have tolerated Simvastatin and Metformin well, patients will receive Fulvestrant at standard doses: 1. Cycle 1: 500mg (in the form of two injections, 1 in each buttock) at Day 1 and Day 15. Each cycle comprises of 28 consecutive days starting from Day 1. 2. Cycle 2 and beyond: 500mg at Day 1 of each 28-day cycle.

Drug: Metformin/Simvastatin/Fulvestrant

Interventions

Metformin/Simvastatin/Fulvestrant DRUG

7 days Lead-in period: Metformin: 850mg (one tablet) twice a day Simvastatin: 20mg (one tablet) once every night Once the doctor has deemed that patients have tolerated Simvastatin and Metformin well, patients will receive Fulvestrant at standard doses: Cycle 1: 500mg (in the form of two injections, 1 in each buttock) at Day 1 and Day 15. Each cycle comprises of 28 consecutive days starting from Day 1. Cycle 2 and beyond: 500mg at Day 1 of each 28-day cycle. Tumour biopsy at 8 weeks. Every 8 weeks for the first 6 months, every 12 weeks thereafter: Performance status evaluation Medical history and physical examination Clinical tumor measurement Review of treatment-related side-effects Blood taking for research purpose and routine blood tests Routine scans

Metformin/Simvastatin/Fulvestrant

Eligibility Criteria

• Age: 18 Years - 99 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Prior treatment with any CDK inhibitor, Fulvestrant, Everolimus, or agent that inhibits the PI3K-mTOR pathway
• Patients with symptomatic visceral disease, or known uncontrolled or symptomatic CNS metastases
• Patients who have not yet recovered from the toxicities of the previous anti-cancer therapy.
• Concurrent administration of other anti-tumor therapies, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy are prohibited. Concomitant bone-modifying agents and gonadotropin-releasing hormone therapy are allowed.
• Major surgery or radiotherapy within 2 weeks of randomization
• Prior stem cell or bone marrow transplantation
• Use of potent CYP3A4 inhibitors or inducers (Table 1); a washout period of 14 days is required for patients discontinuing these medications prior to study enrollment.
• Currently on medications for diabetes (e.g. Metformin, sulphonylureas, insulin) or hypercholesterolaemia (statins or fibrates)
• Renal impairment: Estimated glomerular filtration rate (eGFR) \<60 mL/minute/1.73 m2
• Hepatic impairment: Aspartate transaminase (AST), Alanine Transaminase(ALT) ≥ 2.5 x upper limit of normal range (ULN), OR Total bilirubin ≥ 1.5 x ULN (subjects with Gilbert's syndrome can have bilirubin of up to 1.5 x ULN)
• Pregnancy.
• Breast feeding.
• Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital Singapore

Singapore, 119228, Singapore

RECRUITING

Related Publications (3)

• Park IH, Ro J, Lee KS, Kim EA, Kwon Y, Nam BH, Jung SY, Lee S, Kim SW, Kang HS. Phase II parallel group study showing comparable efficacy between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first-line hormone therapy. J Clin Oncol. 2010 Jun 1;28(16):2705-11. doi: 10.1200/JCO.2009.26.5884. Epub 2010 Apr 26.

  PMID: 20421538 RESULT

• Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011 Nov 20;29(33):4452-61. doi: 10.1200/JCO.2010.34.4879. Epub 2011 Oct 17.

  PMID: 22010023 RESULT

• Massarweh S, Romond E, Black EP, Van Meter E, Shelton B, Kadamyan-Melkumian V, Stevens M, Elledge R. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure. Breast Cancer Res Treat. 2014 Jan;143(2):325-32. doi: 10.1007/s10549-013-2810-9. Epub 2013 Dec 11.

  PMID: 24327334 RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Metformin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Samuel Ow

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Samuel Ow

CONTACT

(65) 6772- 5934; samuel_ow@nuhs.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2017
• First Posted: June 20, 2017
• Study Start: January 20, 2017
• Primary Completion: January 20, 2019
• Study Completion: January 20, 2019
• Last Updated: June 20, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)